Topical composition for treating mucosal lesions with a short gelling time

Abstract

A topical composition for the treatment of mucosal lesions having a short gelling time. The present invention relates to a topical composition comprising a) 0.25-1.5% w / w of hyaluronic acid or a salt thereof, b) 0.01-25% w / w of one or more adhesives, and c) 0.005-0.5% w / w of a non-absorbable antibiotic; a delivery device comprising the same; and its use in medicine, particularly in the treatment and / or prevention of mucosal lesions; in the prevention of post-polypectomy syndrome; as an adjunct therapy to mechanical treatment in gastrointestinal perforation; and as a sealant treatment in surgical anastomoses and leakage or fistulas in the gastrointestinal tract.

Description

[Technical Field]

[0001] This application claims priority to European Patent Application No. EP23382747.6, filed on 20 July 2023.

[0002] The present invention relates to a topical composition comprising hyaluronic acid, one or more adhesives, and a very small amount of a non-absorbable antibiotic, and a delivery device comprising the same. It also relates to its use in medicine, particularly as an endoscopic shield, for treating and / or preventing wounds caused by or associated with endoscopic treatment. [Background technology]

[0003] Endoscopy is a minimally invasive procedure that allows for the diagnosis of internal conditions of the gastrointestinal tract, respiratory tract, or urinary tract using endoscopic instruments inserted through the body's passages. Advances in endoscopic medicine have led to the development of endoscopic treatments, enabling physicians to treat a wide range of conditions using endoscopic techniques, such as the removal of polyps and early-stage tumors.

[0004] Endoscopic polypectomy and hot biopsy have become standard electrosurgical procedures for the removal of small or very small polyps in the colon during colonoscopy. Other techniques, such as endoscopic mucosal resection (EMR) and endoscopic submucosal resection (ESD), allow for the removal of larger polyps or early-stage colorectal cancers, thus reducing the need for surgical intervention.

[0005] While these techniques are generally very safe and convenient, postoperative complications such as bleeding, transmural burns, and perforation still occur in a small number of cases.

[0006] On the other hand, coagulation syndrome (also known as electrocoagulation syndrome after polypectomy and transmural burn syndrome) can occur after electrocoagulation of polyps and refers to the development of abdominal pain, fever, leukocytosis, and peritonitis without obvious perforation.

[0007] On the one hand, massive bleeding may necessitate termination of surgical procedures and require blood transfusions, while postoperative perforation is a particularly severe adverse event that generally requires emergency surgery.

[0008] Therefore, considering the numerous endoscopic treatment procedures performed today, although the number of cases with complications is limited (in percentage), it is essential to try to avoid such complications.

[0009] For example, several approaches have been described to avoid postoperative complications after endoscopic treatment, including clipping techniques after colorectal resection. However, these procedures require special equipment or are very complex, and furthermore, the duration of the clips remains unclear. In addition, polyglycolic acid (PGA) sheets and fibrin adhesive have been described in the art as endoscopic tissue shields for covering wounds after colorectal submucosal dissection (ESD). According to this procedure, several PGA sheets must be placed on the affected tissue using biopsy forceps. After the entire area is covered, fibrin adhesive is sprayed onto it. However, this method is time-consuming and is considered inefficient for covering large mucosal defects.

[0010] International Publication No. 2016135219 discloses a topical composition for use as an endoscope shield for treating wounds caused by endoscopy, comprising hyaluronic acid or a salt thereof, one or more adhesives, and a non-absorbable antibiotic in an amount of 1.5 to 2.5 wt% of the total weight of the composition. These compositions are liquid at room temperature and can be administered to the gastrointestinal mucosa, for example, by using a syringe connected to a catheter that can be introduced via an endoscopic instrument. When these compositions come into contact with the mucosa at body temperature, their viscosity increases and they obtain the consistency of a gel. However, under the inventors' knowledge, these compositions exhibited a relatively long gelation time (around 130 seconds) and limited long-term stability.

[0011] Therefore, there is a need to develop topical compositions that reduce or avoid postoperative complications after endoscopic treatment, contribute to wound healing, and overcome the problems of prior art. [Overview of the project]

[0012] To their surprise, the inventors found that, in the composition disclosed in International Publication No. 2016135219, a significant reduction in the weight percentage of the non-absorbable antibiotic can result in a composition exhibiting optimized long-term stability and a short gelation time.

[0013] As can be seen in the examples, while prior art compositions exhibit a gelation time of around 130 seconds, the compositions according to the present invention exhibit a shorter gelation time, in some cases less than 30 seconds. This is very advantageous because the product can adhere to any position on the mucous membrane without spreading as a liquid, and treatment can begin more quickly.

[0014] In addition, the viscosity of the composition of the present invention at 21°C was found to be lower than that of prior art compositions. This has the advantage that the composition is more fluid and can be administered more easily through injection devices such as syringes. This is because the force required to maintain the movement of the plunger for discharging the contents of the syringe (i.e., dynamic glide force, DGF) is smaller. This makes it possible to use thinner catheters and smaller syringes.

[0015] Furthermore, the compositions of the present invention exhibit improved stability over extended periods compared to prior art formulations containing larger amounts of non-absorbable antibiotics. The findings of the present invention are entirely unexpected. Experts might have anticipated that reducing the amount of non-absorbable antibiotic in the formulation would decrease the gel's stability against bacterial degradation. However, the opposite was found. While not bound by theory, the presence of non-absorbable antibiotics in amounts of approximately 1 wt% or more causes physical instability in the formulation because the non-absorbable antibiotic precipitates. The inventors found that a concentration of 0.005–0.5% w / w of non-absorbable antibiotics is sufficient to provide stability against bacterial degradation of the gel and to improve the physical stability of the formulation over extended periods by avoiding the precipitation of the non-absorbable antibiotic.

[0016] Therefore, a first aspect of the present invention relates to a topical composition particularly suitable for application to the gastrointestinal mucosa or vaginal mucosa, which is, a) 0.25-1.5% w / w hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof, b) One or more adhesives of 0.01-25% w / w, c) 0.005~0.5% w / w non-absorbable antibiotics, Includes; This %w / w percentage is expressed relative to the total weight of the above composition, provided that the sum of the amounts of the above components is equal to or less than 100%.

[0017] Another aspect of the present invention relates to a kit comprising a delivery device and an injection device containing the previously defined topical composition, wherein the delivery device is preferably coupled to the injection device.

[0018] The compositions of the present invention have been demonstrated to reduce ulcer area in in vivo endoscopic studies in rats, as shown in the examples. Therefore, the compositions of the present invention are useful for wound healing and / or for preventing complications arising from such lesions.

[0019] Accordingly, another aspect of the present invention relates to a topical composition as defined above for use in the treatment of mucosal lesions and / or for the prevention of complications arising from mucosal lesions, in particular, where the mucosa is the gastrointestinal mucosa or the vaginal mucosa. This aspect relates to the use of hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof and a non-absorbable antibiotic for the preparation of a topical composition as defined above for topical use in the treatment of mucosal lesions and / or for the prevention of complications arising from mucosal lesions. This may also be formulated as a method for the treatment of mucosal lesions and / or for the prevention of complications arising from mucosal lesions in patients who require it, and includes topical application of a therapeutically effective amount of the previously defined topical composition to patients who require it, including humans.

[0020] In addition, the compositions of the present invention are also useful as sealant treatments in surgical anastomoses in the gastrointestinal tract, such as intestinal anastomoses, which are surgical means to establish communication between two previously distal portions of the intestine and restore intestinal continuity after the removal of a pathological condition affecting the intestine. It is also useful as a sealant treatment for leakage or fistulas in the gastrointestinal tract.

[0021] Thus, another aspect of the present invention relates to a topical composition as defined above for use as a sealant treatment for surgical anastomoses and leakages or fistulas in the gastrointestinal tract. This aspect relates to the use of hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof and a non-absorbable antibiotic for the preparation of a topical composition as defined above for topical use of a sealant treatment for surgical anastomoses and leakages or fistulas in the gastrointestinal tract. This may also be formulated as a method for a sealant treatment for surgical anastomoses and leakages or fistulas in the gastrointestinal tract in patients who require it, this method comprising topically applying a therapeutically effective amount of the topical composition as defined above to a patient who requires it, including a human. [Brief explanation of the drawing]

[0022] [Figure 1]Figure 1 shows the viscosity jump of the formulations of Examples 1 and 3 at a temperature gradient of 21°C to 37°C (V: viscosity, ST step time). [Figure 2] Figure 2 shows the adhesion test used to measure the adhesion of the sample gel (G) to mucin (M) at 37°C.

Mode for Carrying Out the Invention

[0023] All terms used in this specification should be understood in their ordinary meanings known in the art, unless otherwise specified. Other more specific definitions for specific terms used in this application are as shown below and are uniformly applied throughout this application and the claims, and provide a broader definition unless otherwise clearly defining.

[0024] The weight / weight percentage (% w / w) referred to in this specification regarding the components of the composition is expressed as weight (e.g., g) relative to the total weight of the above composition (e.g., g), provided that the sum of the amounts of the components is equal to 100%.

[0025] For the purposes of the present invention, any given range includes both the lower endpoint and the upper endpoint of that range.

[0026] The term "about" or "approximately" when used in this specification refers to a range of values of ±10% of the specified value. For example, the expression "about 10" or "approximately 10" includes ±10% of 10, i.e., 9 to 11.

[0027] The expression "room temperature" when used in this specification means a temperature in the range of 20 to 25°C, particularly a temperature of about 21°C.

[0028] The expression "body temperature" when used in this specification refers to a temperature in the range of 35 to 42°C, particularly 36 to 38°C, especially a temperature of about 37°C.

[0029] This invention relates to topical compositions. For the purposes of this invention, the term "topical" refers to the topical administration of the composition other than systemic (i.e., parenteral and enteral) administration. In particular, this refers to the application of the composition to body surfaces such as mucous membranes, including the oral cavity, gastrointestinal tract, and vaginal mucosa.

[0030] As used herein, "viscosity" refers to a measure of the resistance of a fluid to deformation under shear stress, and describes the internal resistance of a fluid to flow, which can be measured using a rheometer. Rheological tests were performed using a TA Instruments Discovery HR-1 rheometer with a 40 mm parallel plate and a 700 nm gap. First, a preparatory experiment was performed at 21°C for 600 seconds. Subsequently, the test was performed at SR 1s -1 The test was performed at 120s, 21°C viscosity (flow peak hold). Finally, the Peltier temperature was changed to 37°C, and another viscosity test was performed, SR 1s -1 I went 360s.

[0031] Where used herein, the term "adhesion" refers to the ability of the topical compositions of the present invention to adhere, by both chemical and physical means, to a site of topical application or administration, such as a mucous membrane, upon contact, thereby enabling a mechanism for separation once they are in contact. Adhesion can be measured as the force required to remove the gelling formulation from a mucin solution using a texture analyzer TA.XT Plus. For example, a gelling formulation deposited on a cylinder was connected to a mucin solution at a speed of 0.5 mm / s and retracted at a speed of 1 mm / s at 37°C. Adhesion is measured in units of mN / s.

[0032] The terms "molecular weight," "average molecular weight," and "Mw" have the same meaning and are used interchangeably herein. Molecular weight is calculated by the following formula:

number

[0033] For the purposes of this invention, the term "thermally reversible" or equivalent expressions such as "thermally reversible" applied to the composition means that it exhibits reverse thermogellation, i.e., that it undergoes a change in viscosity when the temperature changes. Accordingly, the composition is liquid at room temperature and forms a gel at body temperature. The liquid state at room temperature facilitates the administration of the composition to the target mucosa by using a suitable injection device, such as a syringe or jet injector, which is connected to a delivery device or system, such as a catheter, which can be introduced via an endoscopic instrument. When the composition comes into contact with the mucosa at body temperature, its viscosity increases to a higher viscosity state, thereby achieving gel consistency. This has the advantage that the composition remains on the surface of the affected area.

[0034] In one embodiment, the topical composition is an injectable composition at room temperature that can be administered using a suitable injection device, in combination with one or more of the properties of the various embodiments described above or below, as can be optionally combined.

[0035] As described above, the topical composition of the present invention contains hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof in an amount of 0.25 to 1.5% w / w based on the total weight of the composition.

[0036] Hyaluronic acid (HA) is a naturally occurring anionic, non-sulfated glycosaminoglycan widely distributed throughout connective tissue, epithelial tissue, nerve tissue, and parts of the extracellular matrix. It consists of multiple repeating disaccharide units of N-acetyl-D-glucosamine and D-glucuronic acid. Due to its proliferative and immunomodulatory effects, HA plays a crucial role in tissue repair, inducing tissue repair that promotes healing re-epithelialization instead of scarring.

[0037] There are no restrictions on the types of hyaluronic acid salts that may be used, provided that they are pharmaceutically or veterinarily acceptable when used for therapeutic purposes. The term "pharmaceutically or veterinarily acceptable salt" includes commonly used salts, such as alkali metal salts. Preparation of pharmaceutically acceptable salts of hyaluronic acid can be carried out by methods known in the art. Hyaluronic acid and its salts may differ in some physical properties, but they are equivalent for the purposes of this invention.

[0038] Non-limiting examples of pharmaceutically or veterinarily acceptable salts include inorganic salts such as sodium hyaluronate, magnesium hyaluronate, potassium hyaluronate, zinc hyaluronate, and cobalt hyaluronate, as well as organic salts such as tetrabutylammonium hyaluronate.

[0039] In one embodiment, the topical composition comprises a pharmaceutically or veterinarily acceptable salt of hyaluronic acid, more specifically sodium hyaluronate, in combination with one or more properties of the various embodiments described above or below, as optionally.

[0040] In another embodiment, the topical composition may optionally be combined with one or more properties of the various embodiments described above or below, and may contain hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof, more specifically sodium hyaluronate, in an amount of 0.55 to 1.25% w / w, more specifically about 0.8% w / w, based on the total weight of the topical composition.

[0041] In another embodiment, the topical composition may be optionally combined with one or more properties of the various embodiments described above or below, in a ratio of approximately 0.25% w / w, approximately 0.3% w / w, approximately 0.35% w / w, approximately 0.4% w / w, approximately 0.45% w / w, approximately 0.5% w / w, approximately 0.55% w / w, approximately 0.6% w / w, approximately 0.65% w / w, approximately 0.7% w / w, approximately 0.75% w / w, approximately 0.8% w / w, approximately 0.81% w / w, and approximately It contains hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof, more specifically sodium hyaluronate, in amounts of 0.82% w / w, approximately 0.85% w / w, approximately 0.9% w / w, approximately 0.95% w / w, approximately 1% w / w, 1.05% w / w, approximately 1.1% w / w, approximately 1.15% w / w, approximately 1.2% w / w, approximately 1.25% w / w, approximately 1.3% w / w, approximately 1.35% w / w, approximately 1.4% w / w, approximately 1.45% w / w, or approximately 1.5% w / w.

[0042] In another embodiment, hyaluronic acid or a salt thereof, more specifically sodium hyaluronate, may be optionally combined with one or more properties of the various embodiments described above or below, to have an average molecular weight (Mw) of 5,000 to 1,000,000 Daltons, more specifically, the average molecular weight (Mw) is approximately 5,000, approximately 7,500, approximately 10,000, approximately 15,000, approximately 20,000, approximately 22,500, approximately 25,000, approximately 50,000, approximately 100,000, approximately 200,000, approximately 300,000, approximately 400,000, approximately 500,000, approximately 600,000, approximately 750,000, approximately 800,000, approximately 850,000, or approximately 900,000 Daltons.

[0043] In another embodiment, hyaluronic acid or a salt thereof, more specifically sodium hyaluronate, has an average molecular weight (Mw) of 7,500 to 22,500 daltons, more specifically 10,000 to 20,000 daltons, in combination with one or more properties of the various embodiments described above or below, as optionally.

[0044] In another embodiment, hyaluronic acid or a salt thereof, optionally combined with various one or more of the above or below properties, has an average molecular weight (Mw) of 400,000 to 800,000 daltons, more specifically 500,000 to 750,000 daltons.

[0045] The topical composition of the present invention further comprises one or more adhesives in an amount of 0.01 to 25% w / w relative to the total weight of the above composition. In one embodiment, one or more adhesives are present in an amount of 10 to 25% w / w, more specifically 15 to 25% w / w, and even more specifically about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, and about 20% w / w relative to the total weight of the above composition.

[0046] In another embodiment, optionally combined with one or more properties of the various embodiments described above or below, the weight ratio between one or more adhesives and hyaluronic acid or a salt thereof is 15:1 to 25:1, more specifically 20:1 to 25:1, and even more specifically about 20:1, about 20.5:1, about 20.75:1, about 21:1, about 21.5:1, about 22:1, about 23:1, about 24:1, or about 25:1.

[0047] Non-limiting examples of adhesives that can be used include polyvinyl acetate, cellulose derivatives, sodium alginate, starch, dextrin, polyvinyl alcohol (PVA), (poly)vinyl resin, sodium silicate, and poloxamer. When the adhesive is sodium alginate, compounds containing divalent ions such as CaCl2 are preferably present in the composition.

[0048] Non-limiting examples of cellulose ethers include hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose, propylcellulose, ethylcellulose, 3-O-ethylcellulose, hydroxypropyl methylcellulose phthalate, ethyl(hydroxyethyl)cellulose, cellulose sodium glycolate, 6-O-alkylated cellulose, cellulose octanoate sulfate, cellulose lauroate sulfate, cellulose stearate sulfate and its cationic derivatives, 6-O-benzylcellulose, 2,3-di-O-methyl-6-O-benzylcellulose, 2,3-di-O-benzylcellulose, 2,3-di-O-benzyl-6-O-methylcellulose, 2,3,6-tri-O-benzylcellulose, hydroxypropyl methylcellulose acetate succinate, or O-2-[2-(2-methoxyethoxy)ethoxy]acetylcellulose.

[0049] Hydroxypropyl methylcellulose (HPMC or hypromellose) is a partially O-methylated and O-(2-hydroxypropylated) cellulose ether derivative. It may have a methoxy substitution percentage of 18–35%, more specifically 28–30%, and a hydroxypropoxy content of 4.0–20.0%, more specifically 7–12%. The average molecular weight of HPMC can be measured as a function of its viscosity, thereby such a parameter can vary from 2.4 mPas to 140,000 mPas, more specifically 4 mPas to 120 mPas, and more specifically 10–20 mPas. Its average molecular weight range can be 10,000–1,500,000 Da, more specifically 12,000–100,000 Da, and more specifically 15,000–20,000 Da.

[0050] Methylcellulose (MC) is a methyl ester of cellulose. It can have a percentage of methoxy substitution of 20–55%, more specifically 25–33%. The average molecular weight of MC can range from 10,000–220,000 Datons, more specifically 10,000–20,000 Da.

[0051] Carboxymethylcellulose (CMC) is a carboxymethyl ester of cellulose. It can have a degree of substitution of 0.70 to 0.99, more specifically 0.80 to 0.95. The average molecular weight of MC can range from 100,000 to 1,000,000 daltons, more specifically 250,000 to 750,000 daltons.

[0052] Poloxamers, also known as pluronic compounds, can be nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) (PPO) with two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)) (PEO) on either side. These poloxamers can be collectively named (PEO-PPO-PEO). The polyoxypropylene (PPO) content in poloxamers can be 30-90 wt%, particularly 60-85% w / w. The average molecular weight of poloxamers can be 1000-15000 Da.

[0053] Non-limiting examples of poloxamers include poloxamer 407 (Pluronic® F-127) and poloxamer 188 (Pluronic® F-68). Poloxamer 188 has an average molecular weight of 7,000 to 10,000 Da and contains 75 to 85% w / w ethylene oxide (EO). Poloxamer 407 has an average molecular weight of 9,000 to 15,000 Da and contains 70 to 75% w / w ethylene oxide (EO).

[0054] According to one embodiment, the adhesive is a thermoreversible adhesive, optionally combined with one or more properties of the various embodiments described above or below.

[0055] In another embodiment, one or more adhesives are selected from the group consisting of polyvinyl acetate, cellulose ether, sodium alginate, starch, dextrin, polyvinyl alcohol (PVA), sodium silicate, and poloxamer, in combination with one or more properties of the various embodiments described above or below, as can be optionally selected.

[0056] In another embodiment, the adhesive is an arginate, and the composition further comprises CaCl2, optionally combined with one or more properties of the various embodiments described above or below.

[0057] In another embodiment, one or more adhesives are selected from the group consisting of cellulose ethers, poloxamers, and combinations thereof, in combination with one or more properties of the various embodiments described above or below, as can be optionally selected.

[0058] In one embodiment, the cellulose ether is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylhydroxyethylcellulose, carboxymethylcellulose, propylcellulose, ethylcellulose, 3-O-ethylcellulose, hydroxypropyl methylcellulose phthalate, ethyl(hydroxyethyl)cellulose, cellulose sodium glycolate, 6-O-alkylated cellulose, cellulose octanoate sulfate, cellulose lauroate sulfate, cellulose stearate sulfate and its cationic derivatives, 15 6-O-benzylcellulose, 2,3-di-O-methyl-6-O-benzylcellulose, 2,3-di-O-benzylcellulose, 2,3-di-O-benzyl-6-O-methylcellulose, 2,3,6-tri-O-benzylcellulose, hydroxypropyl methylcellulose acetate succinate, and O-2-[2-(2-methoxyethoxy)ethoxy]acetylcellulose, in combination with one or more properties of the various embodiments described above or below as optionally. More specifically, cellulose ether is present in an amount of 0.01 to 5% w / w, more specifically 0.5 to 2% w / w, relative to the total weight of the above composition.In another embodiment, cellulose ether is present in amounts of approximately 0.01% w / w, 0.05% w / w, 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.62% w / w, 0.7% w / w, 0.75% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.1% w / w, 1.2% w / w, 1.22% w / w, 1.3% w / w, and 1.4% w / w relative to the total weight of the above composition. More specifically, the cellulose ether is present in amounts of approximately 1.5% w / w, approximately 1.6% w / w, approximately 1.62% w / w, approximately 1.63% w / w, approximately 1.7% w / w, approximately 1.8% w / w, approximately 1.9% w / w, approximately 2% w / w, approximately 2.5% w / w, approximately 3% w / w, approximately 3.5% w / w, approximately 4% w / w, approximately 4.5% w / w, or approximately 5% w / w, and is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, and combinations thereof.

[0059] In another embodiment, the cellulose ether is optionally combined with one or more properties of the various embodiments described above or below, in an amount of 0.01 to 5% w / w, more specifically 0.5 to 2% w / w, based on the total weight of the hydroxypropyl methylcellulose, or more specifically, 0.5 to 2% w / w of the composition. In another embodiment, hydroxypropyl methylcellulose is added in amounts of approximately 0.01% w / w, approximately 0.05% w / w, approximately 0.1% w / w, approximately 0.2% w / w, approximately 0.3% w / w, approximately 0.4% w / w, approximately 0.5% w / w, approximately 0.6% w / w, approximately 0.62% w / w, approximately 0.7% w / w, approximately 0.75% w / w, approximately 0.8% w / w, approximately 0.9% w / w, approximately 1% w / w, approximately 1.1% w / w, approximately 1.2% w / w, approximately 1.22% w / w, approximately 1.3% w / w, and approximately 1.4% w / w relative to the total weight of the above composition. It is present in amounts of approximately 1.5% w / w, 1.6% w / w, 1.62% w / w, 1.63% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w, or 5% w / w.

[0060] In another embodiment, the cellulose ether is methylcellulose (MC), in combination with one or more properties of the various embodiments described above or below as optionally chosen, and more specifically, in an amount of 0.01 to 5% w / w, particularly 0.5 to 2% w / w, based on the total weight of the composition. In another embodiment, methylcellulose is added in amounts of approximately 0.01% w / w, 0.05% w / w, 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.62% w / w, 0.7% w / w, 0.75% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.1% w / w, 1.2% w / w, 1.22% w / w, 1.3% w / w, and 1.4% w / w relative to the total weight of the above composition. It is present in amounts of approximately 1.5% w / w, 1.6% w / w, 1.62% w / w, 1.63% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w, or 5% w / w.

[0061] In another embodiment, the poloxamer is selected from the group consisting of poloxamer 407, poloxamer 188, and combinations thereof, in combination with one or more properties of the various embodiments described above or below, as can be optionally selected. More specifically, the poloxamer or poloxamer(s) is present in an amount of 10-22% w / w, more specifically 12-18% w / w, based on the total weight of the composition. In another embodiment, poloxamers or poloxamers are present in amounts of approximately 10% w / w, approximately 11% w / w, approximately 12% w / w, approximately 13% w / w, approximately 14% w / w, approximately 15% w / w, approximately 16% w / w, approximately 16.1% w / w, approximately 16.2% w / w, approximately 16.3% w / w, approximately 16.4% w / w, approximately 16.5% w / w, approximately 17% w / w, approximately 18% w / w, approximately 19% w / w, approximately 20% w / w, approximately 21% w / w, or approximately 22% w / w based on the total weight of the composition.

[0062] In another embodiment, the poloxamer is poloxamer 407, more specifically in an amount of 10-22% w / w, more specifically 12-18% w / w, based on the total weight of the composition, in an optional combination with one or more properties of the various embodiments described above or below. In another embodiment, the poloxamer 407 is present in an amount of about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 16.1% w / w, about 16.2% w / w, about 16.3% w / w, about 16.4% w / w, about 16.5% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, or about 22% w / w, based on the total weight of the composition.

[0063] In another embodiment, the poloxamer is a combination of poloxamer 407 and poloxamer 188, optionally combined with one or more characteristics of the various embodiments described above or below. More specifically, poloxamer 407 is present in amounts of 12-20% w / w, particularly 14-18% w / w, relative to the total weight of the above composition, and more specifically, in amounts of about 14% w / w, 14.5% w / w, about 15% w / w, about 15.5% w / w, about 15.7% w / w, about 15.8% w / w, about 15.9% w / w, about 16% w / w, about 16.1% w / w, about 16.2% w / w, about 16.3% w / w, about 16.4% w / w, about 16.5% w / w, about 17% w / w, about 17.5% w / w, or about 18% w / w relative to the total weight of the above composition; poloxamer 188 is present in amounts of the above composition It is present in amounts of 0.01 to 1% w / w of the total weight of the substance, more specifically 0.1 to 0.6% w / w, and even more specifically, in amounts of approximately 0.18% w / w, approximately 0.19% w / w, 0.2% w / w, approximately 0.21% w / w, approximately 0.22% w / w, approximately 0.23% w / w, approximately 0.24% w / w, approximately 0.25% w / w, approximately 0.3% w / w, approximately 0.35% w / w, approximately 0.4% w / w, approximately 0.41% w / w, approximately 0.42% w / w, approximately 0.43% w / w, approximately 0.44% w / w, approximately 0.45% w / w, approximately 0.5% w / w, approximately 0.55% w / w, or approximately 0.6% w / w of the total weight of the above composition.

[0064] In another embodiment, the poloxamer is a combination of poloxamer 407 and poloxamer 188, in which the weight ratio between poloxamer 407 and poloxamer 188 is 20:1 to 90:1, more specifically 30:1 to 80:1, and even more specifically about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 79:1, or about 80:1, in which case the poloxamer is a combination of poloxamer 407 and poloxamer 188, in which which can be optionally combined with one or more of the characteristics of the various embodiments described above or below.

[0065] In another embodiment, one or more adhesives may be optionally combined with one or more properties of the various embodiments described above or below. i) A cellulose ether, selected from the group consisting particularly hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and combinations thereof, more specifically selected from the group consisting of hydroxypropyl methylcellulose and methylcellulose, in an amount of particularly 0.01 to 5% w / w, more specifically 0.5 to 2% w / w, relative to the total weight of the above composition, and ii) In particular, 10-22% w / w, more specifically 12-18% w / w, of the total weight of the above composition, poloxamers that may be single poloxamers or combinations of poloxamers, especially poloxamer 407 and / or poloxamer 188 Includes.

[0066] In another embodiment, in combination with one or more properties of the various embodiments described above or below, the adhesive comprises a cellulose ether and a poloxamer, wherein the weight ratio of poloxamer to cellulose ether is 5:1 to 40:1, more specifically 5:1 to 30:1, and even more specifically about 5:1, about 10:1, about 15:1, about 20:1, about 25:1, or about 30:1.

[0067] In one embodiment, the topical composition of the present invention comprises two adhesives, optionally combined with one or more properties of the various embodiments described above or below. i) One adhesive is a cellulose ether in an amount of 0.01 to 5% w / w, more specifically 0.5 to 2% w / w, relative to the total weight of the above composition, and is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and combinations thereof, and more specifically from the group consisting of hydroxypropyl methylcellulose and methylcellulose. ii) The other adhesive is poloxamer, particularly poloxamer 407, in an amount of 10-22% w / w, more specifically 12-18% w / w, relative to the total weight of the above composition.

[0068] In one embodiment, the topical composition of the present invention comprises three types of adhesives, optionally combined with one or more properties of the various embodiments described above or below. i) One adhesive is a cellulose ether in an amount of 0.01 to 5% w / w, more specifically 0.5 to 2% w / w, relative to the total weight of the above composition, and is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and combinations thereof, more specifically selected from the group consisting of hydroxypropyl methylcellulose and methylcellulose. ii) The two adhesives are poloxamers, particularly poloxamer 407 and poloxamer 188, wherein the first poloxamer, particularly poloxamer 407, is present in an amount of 12-20% w / w, more specifically 14-18% w / w, relative to the total weight of the composition; and the second poloxamer, particularly poloxamer 188, is present in an amount of 0.01-1% w / w, more specifically 0.1-0.6% w / w, relative to the total weight of the composition.

[0069] The compositions of the present invention are thermoreversible. This means that the compositions of the present invention are liquid compositions at room temperature and gels at body temperature. In particular, when the compositions of the present invention are applied to mucous membranes at body temperature, they form thick films, more specifically films with a thickness of 0.5 to 5 mm, as opposed to thin films. This has the advantage that it further improves the physiological healing process of mucosal lesions.

[0070] In one embodiment, the adhesion of the topical composition at room temperature is lower than the adhesion of the topical composition at body temperature, in combination with one or more properties of the various embodiments described above or below, which can be optionally combined.

[0071] In another embodiment, the viscosity of the topical composition at room temperature is lower than the viscosity of the topical composition at body temperature, in combination with one or more properties of the various embodiments described above or below, as can be optionally combined.

[0072] In another embodiment, the viscosity of the topical composition at body temperature is 50 to 190 Pa·s, more specifically 90 to 150 Pa·s, in combination with one or more properties of the various embodiments described above or below, as optionally combined. More specifically, in this embodiment, the composition contains poloxamer.

[0073] In another embodiment, the topical composition of the present invention is an aqueous composition comprising water or a buffer, optionally combined with one or more properties of the various embodiments described above or below. More specifically, the buffer is phosphate-buffered saline (PBS).

[0074] PBS is a commonly used water-based salt solution with a pH of approximately 7.4, and it contains disodium hydrogen phosphate, sodium chloride, and in some formulations, potassium chloride and potassium dihydrogen phosphate.

[0075] This topical composition contains a non-absorbable antibiotic in an amount of 0.005 to 0.5% w / w relative to the total weight of the composition. The term "non-absorbable antibiotic" refers to a compound having antimicrobial properties that is poorly or not absorbed from the lumen; that is, non-absorbable antibiotics provide activity only locally in the intestine and have negligible systemic absorption. Unlike antibiotics that are available systemically, non-absorbable antibiotics maintain local action without systemic effects and side effects, and because there are no resistant strains, they can allow for long-term repeated treatment. This definition does not include compounds commonly used as disinfectants, such as chlorhexidine.

[0076] In one embodiment, the non-absorbable antibiotic is other than chlorhexidine, optionally combined with one or more of the characteristics of the various embodiments described above or below.

[0077] In another embodiment, the non-absorbable antibiotic is selected from the group consisting of gentamicin, vancomycin, nistatin, neomycin, colistin, kanamycin, polymyxin, and rifaximin, in combination with one or more characteristics of the various embodiments described above or below, as optional. More specifically, the non-absorbable antibiotic is rifaximin.

[0078] In another embodiment, a non-absorbable antibiotic, particularly rifaximin, is present in an amount of 0.01 to 0.4% w / w of the total weight of the composition, more specifically, about 0.01% w / w, about 0.016% w / w, about 0.02% w / w, about 0.05% w / w, about 0.75% w / w, about 0.1% w / w, about 0.12% w / w, about 0.15% w / w, about 0.2% w / w, about 0.24% w / w, about 0.25% w / w, about 0.3% w / w, or about 0.4% w / w of the total weight of the composition.

[0079] The topical compositions of the present invention may also comprise further components, such as mineral cofactors, more specifically cofactors for matrix metalloproteinases (MMPs). As used herein, “cofactor” refers to an agent that activates an enzyme, more specifically, an endopeptidase such as an MMP.

[0080] Examples of mineral cofactors in this preparation include zinc compounds, calcium compounds, manganese compounds, and magnesium compounds. Particularly preferred mineral cofactors are zinc cofactors, such as zinc oxide, zinc gluconate, zinc amino acid chelates, or mixtures thereof.

[0081] In one embodiment, the topical composition may optionally be combined with one or more properties of the various embodiments described above or below to include mineral cofactors, more specifically mineral cofactors for matrix metalloproteinases (MMPs), more specifically zinc cofactors, and even more specifically zinc oxide. The cofactors may be present in the composition in an amount of 4 to 10 wt%, more specifically 6 to 8% by weight, relative to the total weight of the topical composition.

[0082] In one embodiment, the present invention refers to topical compositions, particularly aqueous topical compositions, which can be optionally combined with one or more characteristics of the various embodiments described above or below. a) Hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof, particularly hyaluronic acid salts in amounts of 0.25–1.5% w / w, more specifically 0.55–1.25% w / w; b) one or more adhesives, in particular i) a first adhesive, more specifically in an amount of 0.01 to 5% w / w, more specifically cellulose ether, more specifically hydroxypropyl methylcellulose or methylcellulose; and ii) a poloxamer, more specifically in an amount of 10 to 22% w / w relative to the total weight of the above composition, which may be a single poloxamer or a combination of poloxamers, more particularly poloxamer 407 and / or poloxamer 188; c) Non-absorbable antibiotics in amounts of 0.005-0.5% w / w, more specifically 0.01-0.4% w / w, especially rifaximin. It includes or consists of; The %w / w percentage is expressed relative to the total weight of the above composition, provided that the sum of the amounts of the above components is equal to or less than 100%.

[0083] The topical compositions of the present invention are biodegradable. This means that the topical compositions of the present invention are bioabsorbable, biodegradable, or broken down into components that are better tolerated by the patient's body. Therefore, once applied to the body, there is no need to remove the compositions of the present invention.

[0084] The compositions of the present invention can be prepared by mixing their components, particularly in water or a buffer solution, and stirring until complete dissolution of the components is achieved.

[0085] The composition of the present invention is intended to be administered in a therapeutically effective amount sufficient to cover the affected mucosal area.

[0086] As described above, this also forms a kit comprising a part of an injection device containing a topical composition as already defined, and a delivery device suitable for connection to the injection device.

[0087] This injection device may be any device suitable for containing the composition of the present invention, which is suitable for coupling with or connecting to a delivery device. Non-limiting examples of injection devices include syringes or jet injectors.

[0088] The delivery device can be any tubular device having a lumen that is suitable for being coupled to or connected to an injection device and capable of delivering the composition of the present invention to its site of action. A non-limiting example of a delivery device is a catheter.

[0089] In one embodiment, the delivery device has a diameter smaller than the diameter of the working channel of the endoscopic instrument, optionally combined with one or more characteristics of the various embodiments described above or below.

[0090] For example, when this topical composition is administered to the gastrointestinal mucosa after endoscopic treatment, it can be applied by using a suitable delivery device or system, such as a catheter, which can be introduced via the endoscopic instrument. Therefore, for this therapeutic application, the delivery device has a diameter smaller than the diameter of the working channel of the endoscopic instrument.

[0091] Endoscopic equipment can be the same endoscopic equipment used to perform endoscopic treatment.

[0092] Generally, the working channel of a gastrointestinal endoscope has a diameter in the range of 2.8 to 4.2 mm and a length of approximately 190 cm. In one embodiment, the delivery device has an outer diameter of 4.2 mm or less, more specifically 3.7 mm or less, and a length of 160 cm or more, more specifically over 180 cm. For example, the length of the delivery device may be approximately 190 cm.

[0093] Experienced individuals know that the injection device should be selected depending on the delivery device to be used, so that the composition can be administered by applying the appropriate force.

[0094] For example, in one embodiment, in combination with one or more characteristics of the various embodiments described above or below as optionally, the present invention relates to a delivery device, particularly a catheter, comprising a topical composition as already defined, wherein the delivery device has an inner diameter in the range of 1.4 to 2.2 mm, more specifically 1.6 to 1.8 mm, and the syringe device is a syringe. In this case, the composition can be administered by applying a force of 10 to 70 N. This force is called dynamic glide force (DGF) and is the force required to maintain the movement of the plunger in order to expel the contents of the syringe, and can be measured by a dynamometer.

[0095] In another embodiment, in optional combination with one or more characteristics of the various embodiments described above or below, the present invention relates to a delivery device, particularly a catheter, comprising a topical composition as already defined, wherein the delivery device has a diameter in the range of 0.6 to 0.8 mm, and the injection device is a jet syringe.

[0096] Where used herein, the expression "therapeutic effective dose" refers to an amount of the composition of the present invention that, when administered, is sufficient to prevent or alleviate to some extent the onset of one or more symptoms of the disease being addressed. The specific dose of the topical composition to obtain therapeutic benefit may vary depending on the specific circumstances of the case. A typical amount sprayed is 0.25–2 g / cm³. 2 It is a mucosal lesion.

[0097] For the purposes of the present invention, each component of the topical composition as defined above must be pharmaceutically or veterinarily acceptable in the sense that it is compatible with the other components of the composition. It must also be suitable for use in contact with human and animal tissues or organs with a reasonable benefit-risk ratio, without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications.

[0098] As described above, topical compositions as defined above may be used in the treatment of mucosal lesions and / or for the prevention of complications arising from mucosal lesions.

[0099] The compositions of the present invention are suitable for administration to mucous membranes and / or for the healing of mucosal lesions, in particular burns and, more specifically, mucosal lesions induced by or associated with endoscopic treatment.

[0100] In one embodiment, in optional combination with one or more characteristics of the various embodiments described above or below, the present invention relates to a topical composition as defined above for use in the treatment and / or prevention of mucosal lesions induced by burns, more specifically, burns associated with or caused by endoscopic treatment.

[0101] As used herein, burn means injury caused by any of the following: extreme cold or heat that alters or damages tissue, chemical or electrical burns that alters or damages tissue, or chemical or electrical trauma that alters or damages tissue.

[0102] Generally, endoscopic treatments include polypectomy, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD).

[0103] In another embodiment, the present invention relates to a topical composition as defined above for use in the prevention of post-polypectomy syndrome, in combination with, optionally, one or more characteristics of the various embodiments described above or below.

[0104] In another embodiment, in optional combination with one or more characteristics of the various embodiments described above or below, the present invention relates to topical compositions as defined above for use in the treatment and / or prevention of mucosal lesions selected from the group consisting of gastrointestinal mucosal lesions, vaginal mucosal lesions and oral lesions.

[0105] In another embodiment, optionally combined with one or more characteristics of the various embodiments described above or below, the present invention relates to topical compositions as defined above for use in the treatment and / or prevention of mucosal lesions secondary to radiotherapy (photoproctitis).

[0106] In another embodiment, in optional combination with one or more characteristics of the various embodiments described above or below, the present invention relates to topical compositions as defined above for use in the treatment and / or prevention of mucosal lesions, more specifically gastrointestinal perforation. More specifically, the present invention relates to topical compositions as defined above, which can be used as adjunct therapy to mechanical treatment in gastrointestinal perforation, more specifically gastrointestinal perforation secondary to endoscopy.

[0107] As described above, the topical compositions defined above may also be used as sealants for surgical anastomoses and leaks or fistulas in the gastrointestinal tract, particularly to prevent postoperative leakage.

[0108] As described above, the composition of the present invention exhibits a higher mucosal healing rate and higher physiological healing compared to a composition consisting solely of hyaluronic acid, while simultaneously reducing fibrotic healing.

[0109] As used herein, the term “physiological healing” refers to the recovery of damaged living tissues, organs, and biological systems to normal function. This is the process by which cells throughout the body regenerate and repair themselves, thereby reducing the size of the damaged or necrotic area. The term “fibrotic healing” refers to the temporal and progressive deposition of fibrous tissue over diseased tissue during fibrosis. Generally, when fibrotic healing occurs, scars are formed, which can be difficult to manage and vulnerable to repeated trauma.

[0110] Throughout the specification and claims, the word “comprise” and its variations shall not preclude other technical features, additions, components, or steps. Furthermore, the word “comprise” shall encompass the case of “consisting of.” Further objects, advantages, and characteristics of the present invention may become apparent to those skilled in the art during examination of the specification or may be known through the practice of the present invention. The following examples and drawings are provided for illustrative purposes and shall not limit the present invention. Furthermore, the present invention shall encompass all possible combinations of the specific and preferred embodiments described herein.

[0111] Examples 1.Material Hyaluronic acid (HA) sodium salt: Also known as poly(beta-glucuronic acid (1-3)-beta-N-acetylglucosamine-(1-4). Average molecular weight (0.01-0.02 MDa or 0.5-0.75 MDa) Hydroxymethylpropylcellulose or hypromellose (HPMC). Also known as BonuCel D15H, which has 28-30% methoxy substitution. Methylcellulose (MC): Also known as MethoCel A®, methylcellulose A, or methylcellulose ether. Approximate molecular weight: 14000 g / mol; 27.5-31.5% cellulose with methoxy substitution. Poloxamer 407: Kolliphor® P407 poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol); also known as Pluronic® F127. Oxyethylene content: 71.5-74.9%. Average molecular weight: 9849-14600 g / mol. Poloxamer 188: Kolliphor® P188 poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol); also known as Pluronic® F68. Oxyethylene content 79.9-83.7%; average molecular weight 7680-9510 g / mol. Polyvinyl alcohol (PVA): 87-89% hydrolysis. Average molecular weight 88,000-97,000 g / mol. Arginate: Sodium alginate, also known as alginate. Granulometry 30-150 mesh. Viscosity (1%) (R2, 20 rpm) > 300 cps. CaCl2: Calcium chloride. Molecular weight of calcium chloride dihydrate CaCl22H2O is 147.02 Da. Carboxymethylcellulose (CMC): Carboxymethylcellulose, sodium salt, high viscosity. (2%, H2O, 25℃): 800~3100 mPas. Hydroxyethylcellulose (HEC): Partially O-(2-hydroxyethylated) cellulose. Viscosity (2%, 25℃): 1500~2500 mPa.s Dextran: Dextran from Leuconostoc spp. MR ~40000 g / mol (Specifications: 35000~47000 g / mol) Sodium silicate (Na2SiO3): Sodium silicate solution 13.4-14.4% (titrated with HCl, %NaOH); gravimetric analysis 12.0-13.0% (%Si) Polyvinyl acetate: Poly(vinyl acetate)-GPC shows an average Mw of ~100,000 (beads). Starch: Starch soluble GR for analysis ISO; pH value (2%; water) 6.0-7.5; reducing agent as maltose (max. 0.7%); suitability as an enzyme substrate (for amylase) to pass testing. Rifaximin (RFX): Also known as Rifacol; 4-deoxy-4'-methylpyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV; Molecular weight: C 43 H 51 N3O 11 ;Molecular weight:785.88g / mol

[0112] 2. Protocol for the preparation of this composition On-bench: Protocol 2A Rifaximin (various amounts, see table below) was added to PBS (phosphate-buffered saline, approximately pH 7.4, 100 mL) in a 250 mL glass beaker, and the mixture was stirred at 300 rpm at 50°C. Next, if present, sodium hyaluronate (1 g) was added, and the mixture was stirred at 300 rpm until completely dissolved. Next, cellulose (2 g) was added, and the mixture was stirred again at 300 rpm until completely dissolved. The mixture was placed in a closed container and cooled at 4°C. Finally, a mixture of poloxamers (poloxamer P407 and poloxamer P188, 20 g) or other adhesives was added to the mixture in several batches, and the solids were dispersed by vortexing several times. The container was placed on a roller and stirred at 70 rpm for 2 days. The following composition was then obtained: The amounts of PBS, sodium hyaluronate, cellulose derivative, and adhesive can be increased or decreased as required by the process. [Table 1] [Table 2] [Table 3] [Table 4]

[0113] Further compositions according to the present invention were obtained by following the same protocol as above, except that the poloxamer mixture was replaced with the polymers shown in the table below: [Table 5] [Table 6]

[0114] 3. Characterization of hydrogels Rheology assay Rheology tests were performed using a Discovery HR-1 TA rheometer. First, the sample was prepared at 21°C for 600 seconds. Next, viscosity was measured at 21°C for 120 seconds at a shear rate of 1 s. -1 The measurement was then taken. Afterward, the viscosity was measured at 37°C for 360 seconds at a shear rate of 1 s. -1 The viscosity was measured at [temperature]. The viscosity data was plotted against time, and the gelation time was also determined. Table 7 shows the viscosity data at 37°C obtained for various formulations (letters a and b for each example correspond to different samples of the same formulation). Viscosity at 37°C was determined at 150 seconds (midway through the experiment) and 360 seconds (end of the experiment). [Table 7]

[0115] Viscosity and injectability at 21°C Samples containing 0.01–0.02 MDa of hyaluronic acid (Examples 1 and 2) showed lower viscosity at 21°C than those containing 0.5–0.75 MDa of HA (Examples 3 and 4). This is a particularly good value of less than 1 Pa·s, which relates to the fluidity and injectability of the formulation, and therefore its usefulness. Injectability and fluidity were tested using a texturerometer to determine the injection force that should be applied to a syringe containing the formulation connected to a catheter of a specific length. The results are shown in the table below. [Table 8]

[0116] Table 8 shows that the force required to inject the formulation with lower molecular weight HA (Example 1) was lower than the force applied with higher molecular weight HA (Example 3), even when the catheter was longer.

[0117] Viscosity at 37°C: The optimal viscosity range at 37°C (360 s) was calculated for values ​​above 85 and 200 Pa·s. Table 7 shows the viscosity at 37°C for formulations containing different RFX percentages and different HAs. All formulations showed similar viscosity values ​​within the specification range, meaning that all of them formed a gel at 37°C. When viscosity was determined midway through the experiment (150 s), the viscosity of the samples in Examples 1 and 2 was similar to that obtained at the end of the experiment (360 s). The formulations in Examples 3 and 4 reached their maximum viscosity at the end of the experiment (360 s).

[0118] Gelation time: The difference in viscosity measured at 150 and 360 seconds, observed in Figure 1, is related to the gelation time. Gelation time is defined as the time required to reach maximum viscosity at temperatures from 21°C to 37°C. This time is calculated from the rheological curve. The most preferable gelation time is estimated to be less than 60 seconds. This time is defined for formulations that maintain fluidity along the catheter and immediately gel upon exiting the catheter, remaining attached to the intestinal mucosa. As can be seen in the table, the fastest times correspond to the formulations of Examples 1 and 2: [Table 9]

[0119] Adhesion strength assay To verify that the product adheres to the mucous membrane, formulations with various concentrations of HMPC were tested in adhesion tests according to the method shown in Figure 2. 2 mL of mucin-PBS solution was placed at the top of the cylinder space located at the bottom of the apparatus. The platform was in a 37°C bathroom. The gel sample was placed on the metal cylinder and incubated at 37°C for 2 minutes for gelation. Once the cylinder was connected to the apparatus, the experiment was started by slowly moving the cylinder in the mucin solution at a speed of 0.5 mm / s. When the cylinder received a force of 0.05 N, it stopped in the mucin solution and remained there for 30 seconds. The cylinder was then pulled back at a speed of 1 mm / s. The area along the Y-axis (force in N) and X-axis (time in seconds) provided the adhesion in N / s. This area represents the maximum force and time required for the pull-back. After each test, the mucin solution was replaced. Table 10 shows the data obtained from the adhesion force: [Table 10]

[0120] The formulations of Examples 1 and 6 exhibited adhesive strengths of 28.5 and 30 mN / s, respectively. The formulations of Examples 17-24 also showed adhesive properties, but exhibited higher (Examples 18, 19, 20) or lower viscosity (Examples 17, 21, 22) rheological behavior than poloxamer-derived formulations, demonstrating the versatility of these formulations.

[0121] 4. Evaluation of the susceptibility of the formulation of the present invention to attack Escherichia coli. This study aimed to determine whether formulations with different amounts of RFX were independently more effective at attacking E. coli and E. faecalis.

[0122] experiment: 250 μL of each formulation was dispensed onto a glass disk (12 mm diameter). The test was performed with 3 analytical replicates for each bacterium and test condition. In total, this was done using 48 glass disks on which the control formulation (0% RFX) and test formulations were gelled. The 48 disks with formulations were incubated in an oven at 37 °C for 60 minutes to ensure that they gelled properly. Next, 50 μL of a known quantity of E. coli (1 - 5 x 10 8 cfu / mL) was added to the gelled formulation; the bacterial inoculum was prepared in a liquid medium containing only inorganic salts. Thereafter, the disks with formulations were incubated at 37 °C for 36 hours. The number of viable cells was determined using the serial dilution method and plating of the disks with formulations.

[0123] Quantification of viable bacterial cells after incubation of the formulation with 50 μL of bacterial inoculum at 37 °C for 36 hours is shown in the following table:

Table 11

[0124] A decrease in E. coli was observed after 36 - hour incubation of the bacteria with formulations of various concentrations of RFX (0.12%, 0.40% and 1.20% w / w) at 37 °C, with decreases of 88.75%, 92.65% and 99.94% respectively compared to the control (no RFX, Comparative Example 11).

[0125] 5. Endoscopic Tests in Rats (Tests 1 and 2) The purpose of these experiments was to test the efficacy of the formulation of the present invention. Twelve male Harlan rats (270-300g) were used in Experiments 1 and 2, respectively. The rats were acclimatized for a minimum of 7 days prior to the procedure. The rats were maintained at a constant room temperature (20-22°C) with relative humidity (27-31%) under ventilated conditions in a 12-hour cycle of alternating fluorescent and dark lighting. The rats were individually housed in polycarbonate box cages with free access to water and food (Teklad LM-485 rodent feed). The rats experienced minimal pain and discomfort due to the use of anesthesia. This protocol was approved by the Institutional Animal Care and Use Committee of Hospital Universitari Germans Trials I Pujol. The animals had free access to water, but their food was collected 8 hours before the start of bowel preparation. A rectal enema with saline solution was performed immediately before colonoscopy.

[0126] Rats were anesthetized with isofluorane at a rate of 1.5 mL / min in O2 and subjected to thermal injury using an electrosurgical unit at 40 W for 2 seconds. Two burns were induced in the distal colon of each rat using a "coagrasper" clamp.

[0127] The preparation was administered without mixing it with the contrast agent. These were applied to the mucosal lesion as a covering shield, the catheter was passed through the channel of the endoscopic instrument, and the tip of the catheter was placed over the ulcer. A volume of 1-1.5 mL was administered at approximately 0.5 mL / cm³. 2The study was applied to each animal with mucosal lesions. Colonoscopy was performed using an Olympus Video bronchoscope EVIS EXERA II (BF-1T180) with an outer diameter of 4.9 mm and a working channel of 2.8 mm. Air may be applied for gas injection during endoscopy. Images were obtained through the endoscopic instrument at various times, with emphasis on the area where the pressure ulcer was located. After 7 days, the animals were sacrificed and samples were taken to evaluate mucosal healing. Mucosal healing and regeneration were evaluated as a reduction in mean ulcer area determined using ImageJ software.

[0128] Experiment 1: Three groups of rats were treated with three different formulations. The results are shown in Table 12 below: [Table 12]

[0129] Mucosal healing was observed in all groups. A reduction in ulcer area was observed. In groups G1 and G2, the area was reduced by 55% compared to the initial value. In G3 (comparative example), which contained 1.20% (w / w) RFX (10 times more than G1 and G2), the reduction effect was only 10%. Experiment 2: Two groups of rats were treated with four different formulations. The results are shown in Table 13 below: [Table 13]

[0130] The G1 formulation containing 0.81% w / w HA0.01~0.02MDa and 0.016% w / w RFX achieved a maximum reduction of 88.8% in ulcer area.

[0131] 6. Stability Test The purpose of this study was to obtain data on the stability of the product under realistic storage conditions (5±3°C). For this purpose, the tests were conducted in real time under both storage conditions. Accelerated testing at 40°C was not proposed because the product gelled at 40°C, and no signs of degradation could be observed under these conditions. Samples were stored inside a refrigerator (AR1000CL). Six syringes from each batch (3 for rheology + 3 for HPLC / pH / osmolarity) were stored at 5±3°C. The results (T0=start, T1=1 month; t=2 months; t=3 months; t=4 months) are shown in the table below: [Table 14]

[0132] The formulation with 1.20% w / w RFX (Comparative Example 12) exhibited very low and indeterminate viscosity values ​​(viscosity at t1 decreased relative to t0 but increased at time 3), suggesting that the formulation was unstable due to a lack of homogeneity, likely due to RFX precipitation. In contrast, the trend in viscosity values ​​was maintained for a longer period in the new formulation with 0.016% (w / w). Generally, formulations with higher RFX levels tend to settle over time, resulting in the appearance of pellets corresponding to the precipitated RFX. This is reflected in RFX recovery in HPLC assays: [Table 15]

[0133] The formulation with 1.20% w / w RFX lost 20% of its RFX at t1 and recovered 100% at t4. This discrepancy is a result of sample heterogeneity and precipitation. On the other hand, the formulation with 0.016% w / w RFX maintained its RFX percentage for a longer period.

[0134] List of citations - International Publication No. 2016135219 Pamphlet

[0135] For completeness, various aspects of the present invention are shown in the following numbered clauses: Article 1. a) 0.25-1.5% w / w hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof, b) One or more adhesives of 0.01-25% w / w, c) 0.005~0.5% w / w non-absorbable antibiotics A topical composition comprising; A topical composition in which the above %w / w percentage is expressed relative to the total weight of the composition, provided that the sum of the amounts of the above components is equal to or less than 100%. Clause 2. The topical composition according to Clause 1, wherein the hyaluronic acid or a salt thereof is present in an amount of 0.55 to 1.25% w / w relative to the total weight of the composition. Clause 3. The topical composition according to either Clause 1 or 2, wherein the hyaluronic acid or salt thereof has an average molecular weight of 5,000 to 1,000,000 daltons. Clause 4. The topical composition according to any one of Clauses 1 to 3, wherein the hyaluronic acid or salt thereof is sodium hyaluronate. Clause 5. The topical composition according to any one of Clauses 1 to 4, wherein the adhesive comprises cellulose ether and poloxamer. Clause 6. The topical composition according to Clause 5, wherein the cellulose ether is present in an amount of 0.01 to 5% w / w relative to the total weight of the composition, and the poloxamer is present in an amount of 10 to 22% w / w relative to the total weight of the composition. Clause 7. The topical composition according to any one of Clauses 5 to 6, wherein the cellulose ether is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, and combinations thereof. Clause 8. A topical composition according to any one of Clauses 5 to 7, wherein the poloxamer is selected from poloxamer 407, poloxamer 188, and combinations thereof. Clause 9. The topical composition according to any one of Clauses 1 to 8, wherein the non-absorbable antibiotic is present in an amount of 0.01 to 0.4% w / w relative to the total weight of the composition. Clause 10. The topical composition according to any one of Clauses 1 to 9, wherein the non-absorbable antibiotic is rifaximin. Clause 11. A topical composition according to any one of Clauses 1 to 10, which is an aqueous composition comprising water or a buffer solution. Clause 12. A topical composition according to any one of Clauses 1 to 11, which is an injectionable composition at room temperature. Clause 13. An injection device comprising a topical composition as defined in any of Clauses 1 to 12. Clause 14. A kit comprising an injection device as defined in Clause 13, and a delivery device suitable for connection to the injection device. Clause 15. Topical compositions as defined in any of Clauses 1 to 11, for use in the treatment and / or prevention of mucosal lesions. Clause 16. The topical composition for use described in Clause 15, wherein the mucous membrane is the gastrointestinal mucosa or the vaginal mucosa. Clause 17. A topical composition as defined in any of Clauses 1 to 12, for use in the prevention of post-polypectomy syndrome, or for use as a sealant in surgical anastomoses and leakage or fistulas in the gastrointestinal tract, or for use as an adjunct therapy to mechanical treatment in gastrointestinal perforation.

Claims

1. A topical composition suitable for application on the gastrointestinal mucosa or vaginal mucosa, a) 0.25-1.5% w / w hyaluronic acid or a pharmaceutically or veterinarily acceptable salt thereof, b) One or more adhesives in a concentration of 0.01 to 25% w / w, c) 0.005-0.5% w / w non-absorbable antibiotic and Including; The aforementioned % w / w percentage is expressed relative to the total weight of the composition, provided that the sum of the amounts of the constituent components is equal to or less than 100%. Topical composition.

2. The topical composition according to claim 1, wherein the hyaluronic acid or a salt thereof is present in an amount of 0.55 to 1.25% w / w based on the total weight of the composition.

3. The topical composition according to any one of claims 1 to 2, wherein the hyaluronic acid or salt thereof has an average molecular weight of 5,000 to 1,000,000 daltons.

4. The topical composition according to any one of claims 1 to 3, wherein the hyaluronic acid or salt thereof is sodium hyaluronate.

5. The topical composition according to any one of claims 1 to 4, wherein the adhesive comprises cellulose ether and poloxamer.

6. The topical composition according to claim 5, wherein the cellulose ether is present in an amount of 0.01 to 5% w / w relative to the total weight of the composition, and the poloxamer is present in an amount of 10 to 22% w / w relative to the total weight of the composition.

7. The topical composition according to any one of claims 5 to 6, wherein the cellulose ether is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, and combinations thereof.

8. The topical composition according to any one of claims 5 to 7, wherein the poloxamer is selected from poloxamer 407, poloxamer 188, and combinations thereof.

9. The topical composition according to any one of claims 1 to 8, wherein the non-absorbable antibiotic is present in an amount of 0.01 to 0.4% w / w relative to the total weight of the composition.

10. The topical composition according to any one of claims 1 to 9, wherein the non-absorbable antibiotic is rifaximin.

11. The topical composition according to any one of claims 1 to 10, which is an aqueous composition comprising water or a buffered solution.

12. An injection device comprising the topical composition according to any one of claims 1 to 11.

13. A kit comprising an injection device according to claim 12 and a delivery device suitable for connection to the injection device.

14. A topical composition according to any one of claims 1 to 11 for use in the treatment and / or prevention of mucosal lesions.

15. A topical composition according to any one of claims 1 to 11, for use in the prevention of post-polypectomy syndrome, or for use as a sealant treatment in surgical anastomoses and leakage or fistulas in the gastrointestinal tract, or for use as an adjunct therapy to mechanical treatment in gastrointestinal perforation.

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